Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Publication type

Journal Article


  1. A. Mesut Erzurumluoglu
  2. MengZhen Liu
  3. Victoria E. Jackson
  4. Daniel R. Barnes
  5. Gauri Datta
  6. Carl A. Melbourne
  7. Robin Young
  8. Chiara Batini
  9. Praveen Surendran
  10. Tao Jiang
  11. Sheikh Daud Adnan
  12. Saima Afaq
  13. Arpana Agrawal
  14. Elisabeth Altmaier
  15. Antonis C. Antoniou
  16. Folkert W. Asselbergs
  17. Clemens Baumbach
  18. Laura Bierut
  19. Sarah Bertelsen
  20. Michael Boehnke
  21. Michiel L. Bots
  22. David M. Brazel
  23. John C. Chambers
  24. Jenny Chang-Claude
  25. Chu Chen
  26. Janie Corley
  27. Yi-Ling Chou
  28. Sean P. David
  29. Rudolf A. de Boer
  30. Christiaan A. de Leeuw
  31. Joe G. Dennis
  32. Anna F. Dominiczak
  33. Alison M. Dunning
  34. Douglas F. Easton
  35. Charles Eaton
  36. Paul Elliott
  37. Evangelos Evangelou
  38. Jessica D. Faul
  39. Tatiana Foroud
  40. Alison Goate
  41. Jian Gong
  42. Hans J. Grabe
  43. Jeff Haessler
  44. Christopher Haiman
  45. Göran Hallmans
  46. Anke R. Hammerschlag
  47. Sarah E. Harris
  48. Andrew Hattersley
  49. Andrew Heath
  50. Chris Hsu
  51. William G. Iacono
  52. Stavroula Kanoni
  53. Manav Kapoor
  54. Jaakko Kaprio
  55. Sharon L. Kardia
  56. Fredrik Karpe
  57. Jukka Kontto
  58. Jaspal S. Kooner
  59. Charles Kooperberg
  60. Kari Kuulasmaa
  61. Markku Laakso
  62. Dongbing Lai
  63. Claudia Langenberg
  64. Nhung Le
  65. Guillaume Lettre
  66. Anu Loukola
  67. Jian’an Luan
  68. Pamela A.F. Madden
  69. Massimo Mangino
  70. Riccardo E. Marioni
  71. Eirini Marouli
  72. Jonathan Marten
  73. Nicholas G. Martin
  74. Matt McGue
  75. Kyriaki Michailidou
  76. Evelin Mihailov
  77. Alireza Moayyeri
  78. Marie Moitry
  79. Martina Müller-Nurasyid
  80. Aliya Naheed
  81. Matthias Nauck
  82. Matthew J. Neville
  83. Sune Fallgaard Nielsen
  84. Kari North
  85. Markus Perola
  86. Paul D. P. Pharoah
  87. Giorgio Pistis
  88. Tinca J. Polderman
  89. Danielle Posthuma
  90. Neil Poulter
  91. Beenish Qaiser
  92. Asif Rasheed
  93. Alex Reiner
  94. Frida Renström
  95. John Rice
  96. Rebecca Rohde
  97. Olov Rolandsson
  98. Nilesh J. Samani
  99. Maria Samuel
  100. David Schlessinger
  101. Steven H. Scholte
  102. Robert A. Scott
  103. Peter Sever
  104. Yaming Shao
  105. Nick Shrine
  106. Jennifer A. Smith
  107. John M. Starr
  108. Kathleen Stirrups
  109. Danielle Stram
  110. Heather M. Stringham
  111. Ioanna Tachmazidou
  112. Jean-Claude Tardif
  113. Deborah J. Thompson
  114. Hilary A. Tindle
  115. Vinicius Tragante
  116. Stella Trompet
  117. Valérie Turcot
  118. Jessica Tyrrell
  119. Ilonca Vaartjes
  120. Andries R. van der Leij
  121. Peter van der Meer
  122. Tibor V. Varga
  123. Niek Verweij
  124. Henry Völzke
  125. Nicholas J. Wareham
  126. Helen R. Warren
  127. David R. Weir
  128. Stefan Weiss
  129. Leah Wetherill
  130. Hanieh Yaghootkar
  131. Ersin Yavas
  132. Yu Jiang
  133. Fang Chen
  134. Xiaowei Zhan
  135. Weihua Zhang
  136. Wei Zhao
  137. Kaixin Zhou
  138. Philippe Amouyel
  139. Stefan Blankenberg
  140. Mark J. Caulfield
  141. Rajiv Chowdhury
  142. Francesco Cucca
  143. Ian J. Deary
  144. Panos Deloukas
  145. Emanuele Di Angelantonio
  146. Marco Ferrario
  147. Jean Ferrières
  148. Paul W. Franks
  149. Tim M. Frayling
  150. Philippe Frossard
  151. Ian P. Hall
  152. Caroline Hayward
  153. Jan-Håkan Jansson
  154. J. Wouter Jukema
  155. Frank Kee
  156. Satu Männistö
  157. Andres Metspalu
  158. Patricia B. Munroe
  159. Børge Grønne Nordestgaard
  160. Colin N. A. Palmer
  161. Veikko Salomaa
  162. Naveed Sattar
  163. Timothy Spector
  164. David Peter Strachan
  165. Pim van der Harst
  166. Eleftheria Zeggini
  167. Danish Saleheen
  168. Adam S. Butterworth
  169. Louise V. Wain
  170. Goncalo R. Abecasis
  171. John Danesh
  172. Martin D. Tobin
  173. Scott Vrieze
  174. Dajiang J. Liu
  175. Joanna M. M. Howson

Publication date

June 1, 2020


Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10−8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10−8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10−3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

Published in

Molecular Psychiatry

Volume and page numbers

Volume: 25 , p.2 -2






Open Access

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